Soluble forms of Fibroblast Growth Factor Receptor 1 (FGFR1) have been shown to inhibit tumor cell growth in vitro and in vivo. See, e.g., U.S. Pat. No. 7,678,890. Combining an anti-cancer therapeutic molecule, such as a soluble form of FGFR1, with another anti-cancer therapeutic molecule, can result in antagonistic, additive, or synergistic effects on the efficacy of each of the anti-cancer therapeutics.
The inventors have discovered that administration of an FGFR1 ECD and docetaxel in a mouse xenograft model of non-small cell lung cancer shows synergistic anti-tumor activity of the therapeutic agents. In addition, the inventors have discovered that administration of an FGFR1 ECD and at least one additional therapeutic molecule selected from paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, and bevacizumab, has at least additive activity relative to each molecule administered alone in certain mouse xenograft models.
In some embodiments, methods of treating cancer comprising administering to a subject a fibroblast growth factor receptor 1 (FGFR1) extracellular domain (ECD) and at least one additional therapeutic agent selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, sorafenib, etoposide, topotecan, a vascular endothelial growth factor (VEGF) antagonist, a VEGF trap, an anti-VEGF antibody, and bevacizumab are provided. In some embodiments, the at least one additional therapeutic agent is docetaxel. In some embodiments, the at least one additional therapeutic agent is pemetrexed. In some embodiments, the at least one additional therapeutic agent is cisplatin. In some embodiments, the at least one additional therapeutic agent is paclitaxel. In some embodiments, the at least one additional therapeutic agent is 5-FU. In some embodiments, the at least one additional therapeutic agent is topotecan. In some embodiments, the at least one additional therapeutic agent is viscristine. In some embodiments, the at least one additional therapeutic agents is a VEGF antagonist, such as an anti-VEGF antibody or a VEGF trap. In some embodiments, the at least one additional therapeutic agent is bevacizumab. In some embodiments, the at least one additional therapeutic agent is sorafenib. In some embodiments, the FGFR1 ECD comprises a sequence selected from SEQ ID NOs: 1 to 4.
In some embodiments, methods of treating cancer comprising administering to a subject a fibroblast growth factor receptor 1 (FGFR1) extracellular domain (ECD) fusion molecule and at least one additional therapeutic agent selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, sorafenib, etoposide, topotecan, a vascular epithelial growth factor (VEGF) antagonist, a VEGF trap, an anti-VEGF antibody, and bevacizumab are provided, wherein the FGFR1 ECD fusion molecule comprises an FGFR1 ECD and a fusion partner. In some embodiments, the at least one additional therapeutic agent is docetaxel. In some embodiments, the at least one additional therapeutic agent is pemetrexed. In some embodiments, the at least one additional therapeutic agent is cisplatin. In some embodiments, the at least one additional therapeutic agent is paclitaxel. In some embodiments, the at least one additional therapeutic agent is 5-FU. In some embodiments, the at least one additional therapeutic agent is viscristine. In some embodiments, the at least one additional therapeutic agent is topotecan. In some embodiments, the at least one additional therapeutic agent is a VEGF antagonist, such as an anti-VEGF antibody or a VEGF trap. In some embodiments, the at least one additional therapeutic agent is bevacizumab. In some embodiments, the at least one additional therapeutic agent is sorafenib.
In some embodiments, methods of treating cancer comprising administering to a subject an FGFR1 ECD or FGFR1 ECD fusion molecule and at least two additional therapeutic agents selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, sorafenib, etoposide, topotecan, a vascular epithelial growth factor (VEGF) antagonist, a VEGF trap, an anti-VEGF antibody, and bevacizumab are provided, wherein the FGFR1 ECD fusion molecule comprises an FGFR1 ECD and a fusion partner. In some embodiments, at least one of the two additional therapeutic agents is paclitaxel. In some embodiments, at least one of the two additional therapeutic agents is cisplatin. In some embodiments, at least one of the two additional therapeutic agents is carboplatin. In some embodiments, at least one of the two additional therapeutic agents is oxaliplatin. In some embodiments, at least one of the two additional therapeutic agents is 5-FU. In some embodiments, at least one of the two additional therapeutic agents is doxorubicin. In some embodiments, at least one of the two additional therapeutic agents is etoposide. In some embodiments, at least one of the two additional therapeutic agents is topotecan. In some embodiments, at least one of the two additional therapeutic agents is a VEGF antagonist, such as an anti-VEGF antibody or a VEGF trap. In some embodiments, at least one of the two additional therapeutic agents is bevacizumab. In some embodiments, the two additional therapeutic agents are paclitaxel and carboplatin. In some embodiments, the two additional therapeutic agents are doxorubicin and paclitaxel. In some embodiments, the two additional therapeutic agents are cisplatin and etoposide. In some embodiments, the two additional therapeutic agents are oxaliplatin and 5-FU. In some embodiments, the two additional therapeutic agents are 5-FU and leucovorin. In some embodiments, the two additional therapeutic agents are 5-FU and bevacizumab. In some embodiments, the two additional therapeutic agents are paclitaxel and bevacizumab. In some embodiments, the two additional therapeutic agents are cisplatin and etoposide.
In some embodiments, methods of treating cancer comprising administering to a subject an FGFR1 ECD or FGFR1 ECD fusion molecule and at least three additional therapeutic agents selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, sorafenib, a VEGF antagonist, an anti-VEGF antibody, a VEGF trap, and bevacizumab are provided, wherein the FGFR1 ECD fusion molecule comprises an FGFR1 ECD and a fusion partner. In some embodiments, at least one of the three additional therapeutic agents is oxaliplatin. In some embodiments, at least one of the three additional therapeutic agents is 5-FU. In some embodiments, at least one of the three additional therapeutic agents is leucovorin. In some embodiments, at least one of the three additional therapeutic agents is carboplatin. In some embodiments, at least one of the three additional therapeutic agents is paclitaxel. In some embodiments, at least one of the three additional therapeutic agents is bevacizumab. In some embodiments, the three additional therapeutic agents are oxaliplatin, 5-FU and leucovorin. In some embodiments, the three additional therapeutic agents are bevacizumab, 5-FU and leucovorin. In some embodiments, at least two of the three additional therapeutic agents are cisplatin and etoposide.
The invention also relates, in some embodiments, to a combination of an FGFR1 ECD or FGFR1 ECD fusion molecule and at least one additional therapeutic agent selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, sorafenib, etoposide, topotecan, a vascular endothelial growth factor (VEGF) antagonist, a VEGF trap, an anti-VEGF antibody, and bevacizumab, for treatment of cancer. The invention further relates, in some embodiments to a combination of an FGFR1 ECD or FGFR1 ECD fusion molecule and at least two additional therapeutic agents selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, sorafenib, etoposide, topotecan, a vascular epithelial growth factor (VEGF) antagonist, a VEGF trap, an anti-VEGF antibody, and bevacizumab, for treatment of cancer. The invention also relates, in some embodiments, to a combination of an FGFR1 ECD or FGFR1 ECD fusion molecule and at least three additional therapeutic agents selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, sorafenib, a VEGF antagonist, an anti-VEGF antibody, a VEGF trap, and bevacizumab, for treatment of cancer.
In some embodiments, the FGFR1 ECD and/or FGFR1 ECD fusion molecule is packaged separately from the at least one, at least two, or at least three additional therapeutic agents. In some embodiments, the FGFR1 ECD and/or FGFR1 ECD fusion molecule is not mixed with the at least one, at least two, or at least three additional therapeutic agents prior to administration.
In some embodiments, a method of treating cancer comprising administering to a subject an FGFR1-ECD.339-Fc and docetaxel is provided, wherein the FGFR1-ECD.339-Fc comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, a method of treating cancer comprising administering to a subject an FGFR1-ECD.339-Fc and docetaxel is provided, wherein the FGFR1-ECD.339-Fc consists of the amino acid sequence of SEQ ID NO: 6.
In some embodiments, an FGFR1 ECD or FGFR1 ECD fusion molecule is glycosylated and/or sialylated. In some embodiments, an FGFR1 ECD or the polypeptide portion of the FGFR1 ECD fusion molecule is expressed in Chinese hamster ovary (CHO) cells. In some embodiments, an FGFR1 ECD comprises an amino acid sequence selected from SEQ ID NO: 1 and SEQ ID NO: 3.
In some embodiments, at least one dose of an FGFR1 ECD and/or an FGFR1 ECD fusion molecule and at least one dose of at least one additional therapeutic agent are administered concurrently. In some embodiments, at least one dose of an FGFR1 ECD and/or an FGFR1 ECD fusion molecule and at least one dose of at least one additional therapeutic agent are administered at the same time.
In some embodiments, the FGFR1 ECD comprises an amino acid sequence selected from SEQ ID NOs: 1 to 4. In some embodiments, at least one fusion partner is selected from an Fc, albumin, and polyethylene glycol. In some embodiments, at least one fusion partner is an Fc. In some embodiments, the Fc comprises an amino acid sequence selected from SEQ ID NOs: 8 to 10. In some embodiments, the FGFR1 ECD fusion molecule comprises a sequence selected from SEQ ID NO: 5 and SEQ ID NO: 6. In some embodiments, the at least one fusion partner is an Fc and polyethylene glycol. In some embodiments, the at least one fusion partners is polyethylene glycol. In some embodiments, the fusion molecule comprises a linker between the FGFR1 ECD and one or more fusion partners. In some embodiments, the FGFR1 ECD comprises a signal peptide. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7.
In some embodiments, the FGFR1 ECD fusion molecule is an amount in the range of about 0.5 mg/kg body weight to about 20 mg/kg body weight, such as an amount in the range of about 8 to about 16 mg/kg body weight. In some embodiments, the therapeutically effective amount of the FGFR1 ECD fusion molecule is a dose of about 8 mg/kg body weight, while in some embodiments, the therapeutically effective amount of the FGFR1 ECD fusion molecule is a dose of about 16 mg/kg body weight (or at about 10 mg/kg body weight or about 20 mg/kg body weight, respectively, when calculated using an extinction coefficient of 1.11 mL/mg*cm). In some embodiments, the therapeutically effective amount of FGFR1 ECD fusion molecule is a dose of about 20 mg/kg body weight. In some embodiments, dosages may be administered twice a week, weekly, every other week, at a frequency between weekly and every other week, every three weeks, every four weeks, or every month.
The invention also relates, in some embodiments, to a dosage pack. In some embodiments, a dosage pack comprising at least one component selected from: (i) a fibroblast growth factor receptor 1 (FGFR1) extracellular domain (ECD), (ii) a fibroblast growth factor receptor 1 (FGFR1) extracellular domain (ECD) fusion molecule, and (iii) at least one additional therapeutic agent selected from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, topotecan, a VEGF antagonist, an anti-VEGF antibody, a VEGF trap, bevacizumab, and sorafenib; and instructions for administering an FGFR1 ECD or FGFR1 ECD fusion molecule and the at least one additional therapeutic to a patient is provided. In some embodiments, the instructions included with the dosage pack comprise instructions for administering a therapeutically effective amount of FGFR1 ECD fusion molecule. In some embodiments, the therapeutically effective amount of the FGFR1 ECD fusion molecule is an amount in the range of about 0.5 mg/kg body weight to about 20 mg/kg body weight, such as an amount in the range of about 8 to about 16 mg/kg body weight. In some embodiments, the therapeutically effective amount of the FGFR1 ECD fusion molecule is a dose of about 8 mg/kg body weight. In some embodiments, the therapeutically effective amount of the FGFR1 ECD fusion molecule is a dose of about 16 mg/kg body weight. In some embodiments, the therapeutically effective amount of FGFR1 ECD fusion molecule is a dose of about 20 mg/kg body weight. In some embodiments, dosages may be administered twice a week, weekly, every other week, at a frequency between weekly and every other week, every three weeks, every four weeks, or every month.
In some embodiments, the dosage pack comprises an FGFR1 ECD and does not comprise the at least one additional therapeutic agent, e.g., docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, topotecan, VEGF antagonist, anti-VEGF antibody, VEGF trap, bevacizumab, or sorafenib. In some embodiments, the dosage pack comprises an FGFR1 ECD fusion molecule and does not comprise the at least one additional therapeutic agent, e.g., docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, topotecan, VEGF antagonist, anti-VEGF antibody, VEGF trap, bevacizumab, or sorafenib. In some embodiments, the dosage pack comprises at least one additional therapeutic agent, but does not comprise an FGFR1 ECD or an FGFR1 ECD fusion molecule. In some embodiments, the dosage pack comprises: (i) an FGFR1 ECD or an FGFR1 ECD fusion molecule, and (ii) at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, topotecan, a VEGF antagonist, an anti-VEGF antibody, a VEGF trap, bevacizumab, or sorafenib. In some embodiments, the at least one additional therapeutic agent is docetaxel. In some embodiments, the at least one additional therapeutic agent is pemetrexed. In some embodiments, the at least one additional therapeutic agent is cisplatin. In some embodiments, the at least one additional therapeutic agent is paclitaxel. In some embodiments, the at least one additional therapeutic agent is 5-FU. In some embodiments, the at least one additional therapeutic agent is viscristine. In some embodiments, the at least one additional therapeutic agent is bevacizumab. In some embodiments, the at least one additional therapeutic agent is sorafenib. In some embodiments, the dosage pack comprises at least two additional therapeutic agents, but does not comprise an FGFR1 ECD or an FGFR1 ECD fusion molecule. In some embodiments, the at least two additional therapeutic agents are chosen from docetaxel, paclitaxel, vincristine, carboplatin, cisplatin, oxaliplatin, doxorubicin, 5-fluorouracil (5-FU), leucovorin, pemetrexed, etoposide, topotecan, a VEGF antagonist, an anti-VEGF antibody, a VEGF trap, bevacizumab, and sorafenib.
In some embodiments described above, the FGFR1 ECD or the FGFR1 ECD portion of the FGFR1 ECD fusion molecule comprises a sequence selected from SEQ ID NOs: 1 to 4. In some embodiments, at least one fusion partner is selected from an Fc, albumin, and polyethylene glycol. In some embodiments, at least one fusion partner is an Fc. In some embodiments, the Fc comprises an amino acid sequence selected from SEQ ID NOs: 8 to 10. In some embodiments, the FGFR1 ECD fusion molecule comprises a sequence selected from SEQ ID NO: 5 and SEQ ID NO: 6. In some embodiments, the FGFR1 ECD fusion molecule consists of a sequence selected from SEQ ID NO: 5 and SEQ ID NO: 6. In some embodiments, the at least one fusion partner is an Fc and polyethylene glycol. In some embodiments, the at least one fusion partners is polyethylene glycol.
In certain embodiments, the cancer is prostate cancer, breast cancer, colorectal cancer, lung cancer, endometrial cancer, head and neck cancer, laryngeal cancer, liver cancer, renal cancer glioblastoma or pancreatic cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is renal cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the cancer is prostate cancer.
Any embodiment described herein or any combination of additional therapeutic agents thereof applies to any and all methods of the invention described herein.